Amantadine as a regulator of internal ribosome entry site

Chen, Ying‐Ju; Zeng, Shih-Jhan; Hsu, John; Horng, Jim-Tong; Yang, Hong-Ming; Shih, Shin‐Ru; Chu, Yen-Chang; Wu, Tzong‐Yuan

doi:10.1111/j.1745-7254.2008.00876.x

Cited by 27 publications

(21 citation statements)

References 30 publications

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“…We noted that the effects of dsRNA are similar to that of EMT by reducing the coupling constant between the canonical and noncanonical pathways. To confirm whether the noncanonical pathway was coupled to NF- κ B/RelA through an IRES dependent mechanism, we perturbed an IRES mediated translation using amantadine, a known inhibitor of IRES-dependent translation [46]. A549 cells were activated using poly I:C treatment in the absence or presence of amantadine, and canonical and noncanonical pathway kinetics were measured.…”

Section: Resultsmentioning

confidence: 99%

Systems Approaches to Modeling Chronic Mucosal Inflammation

Kalita

Tian

Gao

et al. 2013

BioMed Research International

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The respiratory mucosa is a major coordinator of the inflammatory response in chronic airway diseases, including asthma and chronic obstructive pulmonary disease (COPD). Signals produced by the chronic inflammatory process induce epithelial mesenchymal transition (EMT) that dramatically alters the epithelial cell phenotype. The effects of EMT on epigenetic reprogramming and the activation of transcriptional networks are known, its effects on the innate inflammatory response are underexplored. We used a multiplex gene expression profiling platform to investigate the perturbations of the innate pathways induced by TGFβ in a primary airway epithelial cell model of EMT. EMT had dramatic effects on the induction of the innate pathway and the coupling interval of the canonical and noncanonical NF-κB pathways. Simulation experiments demonstrate that rapid, coordinated cap-independent translation of TRAF-1 and NF-κB2 is required to reduce the noncanonical pathway coupling interval. Experiments using amantadine confirmed the prediction that TRAF-1 and NF-κB2/p100 production is mediated by an IRES-dependent mechanism. These data indicate that the epigenetic changes produced by EMT induce dynamic state changes of the innate signaling pathway. Further applications of systems approaches will provide understanding of this complex phenotype through deterministic modeling and multidimensional (genomic and proteomic) profiling.

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Section: Resultsmentioning

confidence: 99%

Systems Approaches to Modeling Chronic Mucosal Inflammation

Kalita

Tian

Gao

et al. 2013

BioMed Research International

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“…The relative luciferase activity in RAN 5= UTR reporter-transfected cells was significantly increased compared with that observed in vector-transfected cells (Fig. 6D), and this IRES activity was specifically inhibited by amantadine, an IRES inhibitor (29,30) (Fig. 6E).…”

Section: Ran Is Necessary and Sufficient For Ev71 Replicationmentioning

confidence: 86%

Host MicroRNA miR-197 Plays a Negative Regulatory Role in the Enterovirus 71 Infectious Cycle by Targeting the RAN Protein

Tang

Huang

Chien

et al. 2016

J Virol

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Enterovirus 71 (EV71), a member of Picornaviridae, is associated with severe central nervous system complications. In this study, we identified a cellular microRNA (miRNA), miR-197, whose expression was downregulated by viral infection in a timedependent manner. In miR-197 mimic-transfected cells, EV71 replication was inhibited, whereas the internal ribosome entry site (IRES) activity was decreased in EV71 strains with or without predicted miR-197 target sites, indicating that miR-197 targets host proteins to modulate viral replication. We thus used a quantitative proteomics approach, aided by the TargetScan algorithm, to identify putative target genes of miR-197. Among them, RAN was selected and validated as a genuine target in a 3= untranslated region (UTR) reporter assay. Reduced production of RAN by RNA interference markedly reduced the synthesis of EV71-encoded viral proteins and virus titers. Furthermore, reintroduction of nondegradable RAN into these knockdown cells rescued viral protein synthesis. miR-197 levels were modulated by EV71 to maintain RAN mRNA translatability at late times postinfection since we demonstrated that cap-independent translation exerted by its intrinsic IRES activity was occurring at times when translation attenuation was induced by EV71. EV71-induced downregulation of miR-197 expression increased the expression of RAN, which supported the nuclear transport of the essential viral proteins 3D/3CD and host protein hnRNP K for viral replication. Our data suggest that downregulation of cellular miRNAs may constitute a newly identified mechanism that sustains the expression of host proteins to facilitate viral replication. IMPORTANCEEnterovirus 71 (EV71) is a picornavirus with a positive-sense single-stranded RNA that globally inhibits the cellular translational system, mainly by cleaving cellular eukaryotic translation initiation factor 4G (eIF4G) and poly(A)-binding protein (PABP), which inhibits the association of the ribosome with the host capped mRNA. We used a microRNA (miRNA) microarray chip to identify the host miRNA 197 (miR-197) that was downregulated by EV71. We also used quantitative mass spectrometry and a target site prediction tool to identify the miR-197 target genes. During viral infection, the expression of the target protein RAN was upregulated considerably, and there was a parallel downregulation of miR-197. The nuclear transport of viral 3D/3CD protein and of the host proteins involved in viral replication proceeded in an RAN-dependent manner. We have identified a new mechanism in picornavirus through which EV71-induced cellular miRNA downregulation can regulate host protein levels to facilitate viral replication. M icroRNAs (miRNAs) are a group of endogenous, highly conserved noncoding single-stranded RNAs (ϳ22 nucleotides [nt] in length) that are transcribed from specialized genes and undergo series processing to generate final mature miRNAs. The human genome contains more than 2,580 distinct mature miRNA genes (http://www.mirbase.org/) (1), which act as...

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“…Therefore, the amantadine and ribavirin could be applied to patients infected with ECV 5. It was reported that the amantadine could suppress the IRES mediated translation, and ribavirin is a nucleoside analogue with broad-spectrum antiviral activity by decreasing viral replication in EV71 [23,24]. …”

Section: Discussionmentioning

confidence: 99%

Genetic diversity of a Korean echovirus 5 isolate and response of the strain to five antiviral drugs

Park¹,

Song

Baek³

et al. 2011

Virol J

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An outbreak of echovirus 5 (ECV 5) occurred in Korea in 2006, marking the first time this virus had been identified in the country since enterovirus surveillance began in 1993. Using a sample isolated from a young male patient with aseptic meningitis, we performed sequencing of the Korean ECV 5 strain and compared it with a prototype strain (Noyce). At the nucleotide level, the P1 region (85.3%) had the highest identity value; at the amino acid level, the P3 region (98.0%) had the highest identity value. The two strains shared all cleavage sites, with the exception of the VP1/2A site, which was TY/GA in the Noyce strain but TR/GA in the Korean ECV 5 isolate. In Vero cells infected with the Korean ECV 5 isolate, no cytotoxicity was observed in the presence of azidothymidine, acyclovir, amantadine, lamivudine, or ribavirin, when the drugs were administered at a CC50 value >100 μg/mL. Of the five drugs, only amantadine (IC50: 1 ± 0.42 μg/mL, TI: 100) and ribavirin (IC50: 22 ± 1.36 μg/mL, TI: 4.55) had any antiviral activity against the Korean ECV 5 isolate.

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Amantadine as a regulator of internal ribosome entry site

Cited by 27 publications

References 30 publications

Systems Approaches to Modeling Chronic Mucosal Inflammation

Systems Approaches to Modeling Chronic Mucosal Inflammation

Host MicroRNA miR-197 Plays a Negative Regulatory Role in the Enterovirus 71 Infectious Cycle by Targeting the RAN Protein

Genetic diversity of a Korean echovirus 5 isolate and response of the strain to five antiviral drugs

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